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Anal Cancer: IMRT Reduces Toxicities

SAN FRANCISCO—Anal cancer patients treated with chemotherapy and intensity-modulated radiation therapy (IMRT) in a Phase II cooperative group study had fewer serious side effects than patients treated with chemotherapy and conventional radiation in a previous study, researchers reported at a news conference before the Gastrointestinal Symposium here. Moreover, IMRT appeared to be as effective as conventional radiation for short-term disease control.

Moreover, the trial (Abstract 368), which was designed to test both IMRT's effect on acute toxicity and the feasibility in anal cancer, demonstrated that IMRT is feasible with “very rigorous” real-time quality assurance, Dr. Kachnic continued.

To ensure that all patients treated in the trial received appropriate radiation therapy, she or another lead investigator had to review all radiation plans prior to patient treatment. And the quality assurance step appeared to be important, with 81% of the 52 evaluable cases requiring volume recontouring.

“When we do IMRT of the prostate, the rectum and mesorectum are structures that we want to avoid,” Dr. Kachnic said. “But for anal cancer, it is the primary site where nodes become positive, so we need investigators to contour and treat this area.

“When we saw in the beginning that investigators were having some difficulty, we quickly put out and published—both on the RTOG site and in our Society's number one journal [International Journal of Radiation Oncology • Biology • Physics]—an atlas to help the investigators: Myerson et al: IJROBP 2009;74:824-830).” Dr. Kachnic and colleagues have also been leading education sessions at ASTRO meetings.

“There is definitely a learning curve with IMRT for radiation oncologists,” said the moderator of the news conference, Jennifer C. Obel, MD, Attending Physician and Assistant Professor at NorthShore University Health System in Evanston, Illinois. “I think this trial actually demonstrates that we can handle that learning curve very easily through quality assurance.”

Sixty-three patients with non-metastatic squamous cell anal cancer, Stage T2N0 or above, enrolled in the trial between 2006 and 2008. Patients received two cycles of 5-FU and mitomycin-C followed by dose-painted IMRT. The IMRT dose was based on tumor stage, with more advanced cancers receiving higher doses.

With a median follow-up of 26.7 months, 52 patients were evaluable. The clinical complete response rate was 64% at eight weeks after therapy and 81% at 12 weeks.

To get an idea of how IMRT compared with standard radiation in terms of toxicity and efficacy, Dr. Kachnic and colleagues compared the results in the current trial, RTOG0592, with those from the 5FU-mitomycin-C arm of a previous trial, RTOG9811.

The overall Grade 2 and above gastrointestinal and genitourinary side effects were similar in the two trials. (The primary aim of the current trial was to see a 15% reduction in Grade 2 or higher GI and GU toxicity, and was not met.)

However, the proportion of patients who developed Grade 3 or higher GI side effects was significantly reduced, from approximately 35% to 20%. Additionally, there was a slight reduction in Grade 2 and above dermatologic side effects, and a substantial reduction of Grade 3 or higher dermatologic side effects, from approximately 48% to 22%. Unexpectedly, there was also a small drop in the rate of hematologic side effects, although the change appeared to be mostly a reduction in Grade 2 toxicities.

IMRT did not appear to compromise disease control at two years. When compared with the patients treated with conventional radiation in RTOG9811, the IMRT-treated patients had similar rates of local-regional failure (19% in each study), colostomy failure (8% in IMRT vs 11% with conventional radiation), overall survival (86% vs 91%), disease-free-survival (77% vs 75%), colostomy free survival (84% vs 83%), and distant failure (14% vs 9%). None of the differences were statistically significant, and Dr. Kachnic speculated that numerical differences in overall survival and distant failure might have been due to a larger proportion of node-positive patients in the current trial.

Future Studies

When questioned directly about whether she was suggesting that IMRT is as good as conventional radiation based on this cross-trial comparison, Dr. Kachnic said that was not the point. “The goal of this study was not to, in a randomized Phase III fashion, compare the efficacy between the two types of radiation. It was really to test the feasibility and to reduce the acute toxicities.”

Based on the data from the current trial, future RTOG studies may employ IMRT in combination with other agents that might enhance toxicity, with the goal of improving disease-free survival without an overall increase in toxicity.

Dr. Obel concurred with that approach. She pointed out that the majority of patients with anal cancer are cured with chemotherapy and radiation alone, but that acute toxicities can interfere with therapy. “IMRT has fewer short-term side effects,” she said. “So if we want to add on other agents, this might be a more reasonable platform so that toxicities don't occur.”

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